Novel process for making compounds for use in the treatment of cancer

ABSTRACT

Disclosed herein is a process of making a compound of formula I 
     
       
         
         
             
             
         
       
     
     The compound of formula I is an inhibitor of MEK and thus can be used to treat cancer.

PRIORITY CLAIM

This application is a continuation of PCT Application No.PCT/US2013/064866, filed Oct. 14, 2013, which claims the benefit ofpriority to U.S. Application Ser. No. 61/713,104, filed Oct. 12, 2012.The entire contents of the aforementioned application are incorporatedherein by reference.

FIELD OF THE INVENTION

The invention relates to a process for making certain compounds thatinhibit MEK that are useful for the treatment of hyperproliferativedisorders such as cancer. Such compounds are described in WO2007044515,the entire contents of which is incorporated by reference, and in ACSMed. Chem Lett., 2012, 3, 416-421.

BACKGROUND OF THE INVENTION

Like Abl kinase inhibition, MEKI (MAPK/ERK Kinase) inhibition representsa promising strategy for treating cancers caused by aberrant ERK/MAPKpathway signaling (Solit et al., 2006; Wellbrock et al., 2004). TheMEK-ERK signal transduction cascade is a conserved pathway whichregulates cell growth, proliferation, differentiation, and apoptosis inresponse to growth factors, cytokines, and hormones. This pathwayoperates downstream of Ras which is often upregulated or mutated inhuman tumors. MEK is a critical effector of Ras function. The ERK/MAPKpathway is upregulated in 30% of all tumors, and oncogenic activatingmutations in K-Ras and B-Raf have been identified in 22% and 18% of allcancers respectively (Allen et al., 2003; Bamford S, 2004; Davies etal., 2002; Malumbres and Barbacid, 2003). A large portion of humancancers, including 66% (B-Raf) of malignant melanomas, 60% (K-Ras) and4% (B-Raf) of pancreatic cancers, 50% of colorectal cancers (colon, inparticular, K-Ras: 30%, B-Raf: 15%), 20% (K-Ras) of lung cancers, 27%(B-Raf) papillary and anaplastic thyroid cancer, and 10-20% (B-Raf) ofendometriod ovarian cancers, harbor activating Ras and Raf mutations.Inhibition of the ERK pathway, and in particular inhibition of MEKkinase activity, results in anti-metastatic and anti-angiogenic effectslargely due to a reduction of cell-cell contact and motility as well asdownregulation of vascular endothelial growth factor (VEGF) expression.Furthermore, expression of dominant negative MEK or ERK reduced thetransforming ability of mutant Ras as seen in cell culture and inprimary and metastatic growth of human tumor xenografts in vivo.Therefore, the MEK-ERK signal transduction pathway is an appropriatepathway to target for therapeutic intervention and compounds that targetMEK present considerable therapeutic potential.

Accordingly, there is an ongoing need for the identification ofcompounds that inhibit MEK for the treatment of cancer as well asprocesses for making such compounds.

SUMMARY OF THE INVENTION

Provided herein is a process for making compounds of formula I:

wherein:

Ring A is arylene or heteroarylene optionally substituted with one, two,three, or four groups selected from R⁶, R⁷, R⁸, and R⁹, each of whichare independently selected from hydrogen, halo, (C₁-C₈)alkyl,halo(C₁-C₈)alkyl, hydroxy, (C₁-C₆)alkoxy, and halo(C₁-C₆)alkoxy;

X is alkyl, halo, halo(C₁-C₈)alkyl, or halo(C₁-C₆)alkoxy;

R¹, R², R³, and R⁴ are each independently hydrogen, (C₁-C₈)alkyl, orhalo(C₁-C₈)alkyl;

R⁵ is hydrogen, halo, or (C₁-C₈)alkyl; comprising:

contacting a compound of formula II_(a)-1 with a compound of formulaII-1 to provide a compound of formula I, wherein X and R⁵ are as definedabove, and wherein R¹⁰ is F, Br, Cl, or —OSO₂—CF₃ and R¹¹ is H or aprotecting group.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

The following abbreviations and terms have the indicated meaningsthroughout:

Abbreviation Meaning Ac Acetyl Aq Aqueous Ar Argon BocTert-butoxycarbonyl Br Broad ° C. Degrees Celsius c− Cyclo calcdCalculated CBZ CarboBenZoxy = benzyloxycarbonyl d Doublet dd Doublet ofdoublets ddd Doublet of doublets of doublets dt Doublet of triplets DMFN,N-Dimethylformamide DMSO Dimethyl sulfoxide Dppf1,1′-bis(diphenylphosphano)ferrocene EA Elemental Analysis EI ElectronImpact ionization eq Equivalent Fmoc Fluorenylmethyloxycarbonyl gGram(s) h or hr Hour(s) HPLC High pressure liquid chromatography H₂Hydrogen L Liter(s) LiHMDS Lithium bis(trimethylsilyl)azide M Molar ormolarity m Multiplet MHz Megahertz (frequency) Min Minute(s) mLMilliliter(s) Mp Melting point m/z Mass to charge ratio μL Microliter(s)Mol Mole(s) MS Mass spectral analysis N₂ Nitrogen N Normal or normalitynM Nanomolar NMR Nuclear magnetic resonance spectroscopy Pd/C Palladiumon carbon Q Quartet RT Room temperature s Singlet soln Solution S/CSubstrate/catalyst ratio t or tr Triplet THF Tetrahydrofuran TLC Thinlayer chromatography v/v Volume to volume

The symbol “−” means a single bond, “=” means a double bond.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to have hydrogen substitutionto conform to a valence of four. For example, in the structure on theleft-hand side of the schematic below, there are nine hydrogens implied.The nine hydrogens are depicted in the right-hand structure. Sometimes aparticular atom in a structure is described in textual formula as havinga hydrogen or hydrogens as substitution (expressly defined hydrogen),for example, —CH₂CH₂—. It is understood by one of ordinary skill in theart that the aforementioned descriptive techniques are common in thechemical arts to provide brevity and simplicity to description ofotherwise complex structures.

If a group “R” is depicted as “floating” on a ring system, as forexample in the formula:

then, unless otherwise defined, a substituent “R” may reside on any atomof the ring system, assuming replacement of a depicted, implied, orexpressly defined hydrogen from one of the ring atoms, so long as astable structure is formed.

If a group “R” is depicted as floating on a fused ring system, as forexample in the formulae:

then, unless otherwise defined, a substituent “R” may reside on any atomof the fused ring system, assuming replacement of a depicted hydrogen(for example the —NH— in the formula above), implied hydrogen (forexample as in the formula above, where the hydrogens are not shown butunderstood to be present), or expressly defined hydrogen (for examplewhere in the formula above, “Z” equals ═CH—) from one of the ring atoms,so long as a stable structure is formed. In the example depicted, the“R” group may reside on either the 5-membered or the 6-membered ring ofthe fused ring system. When a group “R” is depicted as existing on aring system containing saturated carbons, as for example in the formula:

where, in this example, “y” can be more than one, assuming each replacesa currently depicted, implied, or expressly defined hydrogen on thering; then, unless otherwise defined, where the resulting structure isstable, two “R's” may reside on the same carbon. A simple example iswhen R is a methyl group, there can exist a geminal dimethyl on a carbonof the depicted ring (an “annular” carbon). In another example, two R'son the same carbon, including that carbon, may form a ring, thuscreating a spirocyclic ring (a “spirocyclyl” group) structure with thedepicted ring as for example in the formula:

“Halogen” or “halo” refers to fluorine, chlorine, bromine, or iodine.

“Alkyl” refers to a branched or straight hydrocarbon chain of one toeight carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl, hexyl, and heptyl. (C₁-C₆)alkyl ispreferred.

“Alkoxy” refers to a moiety of the formula —OR^(a), wherein R^(a) is an(C₁-C₆)alkyl moiety as defined herein. Examples of alkoxy moietiesinclude, but are not limited to, methoxy, ethoxy, isopropoxy, and thelike.

“Alkoxycarbonyl” refers to a group —C(O)—R^(b) wherein R^(b) is(C₁-C₆)alkoxy as defined herein.

“Aryl” means a monovalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. Unless statedotherwise, the valency of the group may be located on any atom of anyring within the radical, valency rules permitting. Representativeexamples include phenyl, naphthyl, and indanyl, and the like.

“Arylene” means a divalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. Representativeexamples include phenylene, naphthylene, and indanylene, and the like.

“(C₃-C₈)Cycloalkyl” refers to a single saturated carbocyclic ring ofthree to eight ring carbons, such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. Cycloalkyl may optionally be substitutedwith one or more substituents, preferably one, two, or threesubstituents. Preferably, cycloalkyl substituent is selected from thegroup consisting of (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, halo, amino, mono- anddi(C₁-C₆)alkylamino, hetero(C₁-C₆)alkyl, acyl, aryl, and heteroaryl.

“Cycloalkyloxycarbonyl” means a group —C(O)—OR^(c) wherein R^(c) is(C₃-C₆)cycloalkyl as defined herein.

“Phenyloxycarbonyl” refers to a group —C(O)—Ophenyl.

“Heteroaryl” means a monocyclic, fused bicyclic, or fused tricyclic,monovalent radical of 5 to 14 ring atoms containing one or more,preferably one, two, three, or four ring heteroatoms independentlyselected from —O—, —S(O)_(n)— (n is 0, 1, or 2), —N—, —N(R^(x))—, andthe remaining ring atoms being carbon, wherein the ring comprising amonocyclic radical is aromatic and wherein at least one of the fusedrings comprising a bicyclic or tricyclic radical is aromatic. One or tworing carbon atoms of any nonaromatic rings comprising a bicyclic ortricyclic radical may be replaced by a —C(O)—, —C(S)—, or —C(═NH)—group. R^(x) is hydrogen, alkyl, hydroxy, alkoxy, acyl, oralkylsulfonyl. Unless stated otherwise, the valency may be located onany atom of any ring of the heteroaryl group, valency rules permitting.In particular, when the point of valency is located on the nitrogen,R^(x) is absent. More specifically, the term heteroaryl includes, but isnot limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl,pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl,2,3-dihydro-1H-indolyl (including, for example,2,3-dihydro-1H-indol-2-yl or 2,3-dihydro-1H-indol-5-yl, and the like),isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl,benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl,phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl,quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl (including, for example,tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, and the like),pyrrolo[3,2-c]pyridinyl (including, for example,pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like),benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl,benzothienyl, and the derivatives thereof, or N-oxide or a protectedderivative thereof.

“Heteroarylene” means a monocyclic, fused bicyclic, or fused tricyclic,divalent radical of 5 to 14 ring atoms containing one or more,preferably one, two, three, or four ring heteroatoms independentlyselected from —O—, —S(O)_(n)— (n is 0, 1, or 2), —N—, —N(R¹⁹)—, and theremaining ring atoms being carbon, wherein the ring comprising amonocyclic radical is aromatic and wherein at least one of the fusedrings comprising a bicyclic or tricyclic radical is aromatic. One or tworing carbon atoms of any nonaromatic rings comprising a bicyclic ortricyclic radical may be replaced by a —C(O)—, —C(S)—, or —C(═NH)—group. R¹⁹ is hydrogen, alkyl, or alkenyl. Unless stated otherwise, thevalencies may be located on any atom of any ring of the heteroarylenegroup, valency rules permitting. In particular, when the point ofvalency is located on the nitrogen, R^(x) is absent. More specifically,the term heteroaryl includes, but is not limited to, thien-diyl,benzo[d]isoxazol-diyl, benzo[d]isothiazol-diyl, 1H-indazol-diyl(optionally substituted at the N1 position with IV),benzo[d]oxazol-diyl, benzo[d]thiazol-diyl, 1H-benzo[d]imidazol-diyl(optionally substituted at the N1 position with R¹⁹),1H-benzo[d][1,2,3]triazol-diyl (optionally substituted at the N1position with R¹⁹), imidazo[1,2-a]pyridin-diyl, cinnolin-diyl,quinolin-diyl, pyridin-diyl, 1-oxido-pyridin-diyl,[1,2,4]triazolo[4,3-a]pyridin-diyl, and2,3-dihydroimidazo[1,2-a]pyridin-diyl, and the like.

“Heterogeneous transition metal hydrogenation catalyst” (hydrogenationcatalyst) refers to a transition metal hydrogenation catalyst which actsin a different phase than the substrate. Especially the transition metalhydrogenation catalyst is in the solid phase. The “support” can bemerely a surface on which the metal is spread to increase the surfacearea. The supports are porous materials with a high surface area, mostcommonly alumina or various kinds of carbon. Further examples ofsupports include, but are not limited to, silicon dioxide, titaniumdioxide, calcium carbonate, barium sulfate, diatomaceous earth, andclay. The metal itself can also act as a support, if no other support ispresent. More specifically the term “heterogeneous transition metalhydrogenation catalyst” includes but is not limited to, a Raneycatalyst, Pd/C, Pd(OH)₂/C, Pd(OAc)₂ polyurea microcapsules (NP Pd(0)Encat™ 30), Au/TiO₂, Rh/C, Ru/Al₂O₃, Ir/CaCO₃, and Pt/C, or a mixturethereof. NP Pd(0) Encat™ 30 is Palladium(0), microencapsulated inpolyurea matrix, and is available from Sigma Aldrich as Product Number653667. This catalyst is available as a 45 percent mixture ofnanoparticles of palladium approximately 2 nm in size in water,typically containing 0.4 mmol/g Pd(0) (dry basis), where the unit weightincludes the weight of water. See Ley, S. V. et. al. Org Lett. 2003 Nov.27; 5(24):4665-8. In a particular embodiment, the “heterogeneoustransition metal hydrogenation catalyst” is not pre-treated withsulphide.

“Strong base” refers to conjugate bases of weak acids with a pK_(a)>13such as alkali metal salts of carbanion, alkoxides, amides, hydroxides,and hydrides, in particular the strong bases are lithium, sodium,potassium, rubidium, or cesium salts of carbanion, alkoxides, amides,hydroxides, and hydrides. More particularly strong base according to theinvention refers to sodium, potassium, or lithium amide or phenylithium,most particularly to butyllithium, t-butyllithium, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, lithiumdiethylamide, potassium t-butoxide, lithium t-butoxide, sodium amide,and sodium hydride. Even more particularly, the strong base isbutyllithium, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, or lithium diethylamide.

“Strong acid” refers to an acid that dissociates completely in anaqueous solution with a pH≤2. The strong acids include, but are notlimited to: sulphuric acid (H₂SO₄), hydrohalogenic acid (i.e. HX″wherein X″ is I, Br, Cl or F), nitric acid (HNO₃), phosphoric acid(H₃PO₄), and combinations thereof. Particularly, the strong acid isH₂SO₄ or hydrohalogenic acid, wherein X″ is Br or Cl. Most particularly,the strong acid is HCl. Particularly the concentration of HCl in wateris in the range of 10% to 90%, more particularly 20% to 40%, mostparticularly 37%.

“Amino protecting groups” refers to an acid or base labile aminoprotecting groups, such as C₁-C₆alkoxycarbonyl,C₃-C₆cycloalkyloxycarbonyl, phenyloxycarbonyl, or toluenesulfonyl. Inparticular, examples of “amino protecting groups” include, but are notlimited to, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz),p-Toluenesulfonyl (Ts), and fluorenylmethyloxycarbonyl (FMoc). Inparticular, “amino protecting groups” refers to tert-butoxycarbonyl.(See Peter G. M. Wuts & Theodora W. Greene, Greene's Protective Groupsin Organic Synthesis, 4^(th) ed. (2006)).

Particularly, for the terms which definitions are given above are thosespecifically exemplified in the Examples.

“Yield” for each of the reactions described herein is expressed as apercentage of the theoretical yield.

Any one of the process steps or sequences disclosed and/or claimedherein can be performed under an inert gas atmosphere, more particularlyunder argon or nitrogen. In addition, the methods of the presentinvention may be carried out as semi-continuous or continuous processes,more preferably as continuous processes.

Moreover, many of the process steps and sequences that are describedherein can be telescoped.

Embodiments of the Invention

In one aspect, the present invention provides a process for preparing acompound of formula I, comprising contacting a compound of formulaII_(a)-1 with a compound of formula II-1, wherein X and R⁵ are asdefined above, and wherein R¹⁰ is F, Cl, Br, I, or —OSO₂—CF₃ and theother variables are as previously defined.

In one embodiment, X and R⁵ in a compound of formula II-1 are eachindependently F, Cl, Br, or I. In another embodiment, X is F and R⁵ isI.

In one embodiment, the compound of formula II-1 is the compound offormula II-2,

wherein R¹¹ is as H or a protecting group and Ring A is optionallysubstituted with one, two, three, or four groups selected from R⁶, R⁷,R⁸, and R⁹, each of which are independently selected from halo,(C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₁-C₆)alkoxy, and halo(C₁-C₆)alkoxy.

In a particular embodiment of the present invention, Ring A is phenyl orpyridyl. More particularly, Ring A is phenyl substituted with R^(12a)and R^(12b) which are each independently F, Cl, Br, I, alkyl, haloalkyl,alkoxy, or haloalkoxy.

In another embodiment, the compound of formula II-1 is the compound offormula II-3,

wherein R¹¹ is as defined previously and R¹⁰ is F, Cl, Br, I, orOSO₂CF₃, and R^(12a) and R^(12b) are each independently F, Cl, Br, I,alkyl, haloalkyl, alkoxy, or haloalkoxy.

In one embodiment of the compound of formula II-1, II-2, or II-3, R¹⁰ isF, Cl, Br, or I, and R^(12a) and R^(12b) are each independently F, Cl,Br, I, alkyl, haloalkyl, alkoxy, or haloalkoxy.

In another embodiment of the compound of formula II-1, II-2, or II-3,R¹⁰ is F and R^(12a) and R^(12b) are each independently F, Cl, I, alkyl,or alkoxy.

In another embodiment the compound of formula II-1, II-2 or II-3, R¹⁰ isF and R^(12a) and R^(12b) are each independently F, Cl, I, or alkyl.

In one embodiment, the present invention provides a process forpreparing a compound of formula I′, comprising contacting a compound offormula II_(a) with a compound of formula II, the synthesis of which isdescribed below.

In another embodiment, the present invention provides a process forpreparing a compound of formula I′, comprising contacting a compound offormula II_(a) with a compound of formula II in the presence of a strongbase. In a particular embodiment, the strong base is selected from thegroup consisting of butyllithium, t-butyllithium, the lithium, sodium,or potassium salts of mono or bis substituted alkyl or aromatic amines,and silylalkyl or silylaromatic amines.

In a more particular embodiment, the strong base is selected from thegroup consisting of the lithium, sodium, or potassium salts ofdiisopropyl amine, bis(trimethylsilyl)amine, diethylamine, anddimethylamine.

In another embodiment, the strong base is selected from the groupconsisting of the lithium, sodium, and potassium salts ofbis(trimethylsilyl)amine.

In another embodiment, the strong base is selected from the groupconsisting of lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, and lithium diethylamide. More particularly,the base is lithium bis(trimethylsilyl)amide.

The skilled artisan will understand that in these and other embodiments,the strong base can be obtained commercially or generated in situ usingconventional methods.

The reaction of a compound of formula II with a compound of formulaII_(a) is typically performed in the presence of a solvent. Typically,the solvent is selected from the group consisting of a an ether-likesolvent (e.g., tetrahydrofuran, diisopropyl ether, t-butylmethyl ether,dibutyl ether, dimethyl acetal, dioxane, or 2-methyl tetrahydrofuran(2-MeTHF)); an aromatic solvent (e.g., toluene or t-butyl-benzene), analiphatic hydrocarbon solvent (e.g., hexanes, heptanes, or pentane); asaturated alicyclic hydrocarbon solvent (e.g., cyclohexane orcyclopentane); and a polar aprotic solvent (e.g., dimethylformamide ordimethyl sulfoxide), or a mixture thereof. Preferred solvents includetoluene and tetrahydrofuran. In a particular embodiment, the solvent istetrahydrofuran.

The compound of formula II_(a) is generally commercially available or isreadily prepared using methods well known to the person skilled in theart. For example, the compound of formula II_(a) is available from SigmaAldrich as 2-fluoro-4-iodo-aniline (CAS Registry Number (CASRN)29632-74-4).

In a typical procedure, a strong base such as lithiumbis(trimethylsilyl) amide (LiHMDS) is added to mixture of a compound offormula II-1 such as a compound of formula H and 2-fluoro-4-iodo anilinein a suitable ether-like solvent such as THF. The reaction mixture istypically quenched with aqueous acid, typically aqueous sulphuric acidor hydrochloric acid, and then worked-up according to conventionalmethods to provide a compound of formula I such as a compound of formulaI′.

In another embodiment, the present invention provides a process forpreparing a compound of formula II, comprising deprotecting a compoundof formula III.

In one embodiment, the deprotection is accomplished in a suitablesolvent using H₂ in the presence of a heterogeneous hydrogenationtransition metal catalyst, or by treatment with chloroethylchloroformate in the presence of MeCN or Na/NH₃. Preferably, thedeprotection occurs by catalytic hydrogenolysis in the presence of amineral acid such as HCl or an organic acid such as acetic acid or amixture thereof, which accelerates the reaction. More particularly, thedeprotection is accomplished via hydrogenolysis in the presence of asuitable solvent and in the presence of an acid such as hydrochloricacid or acetic acid or a mixture thereof. Most particularly, thedeprotection is accomplished in the presence of HCl and acetic acid.

The heterogeneous hydrogenation transition metal catalyst can be anysuch catalyst known in the art. The catalyst is typically aheterogeneous transition metal catalyst which is typically selected fromthe group consisting of a Raney catalyst, Pd/C, Pd(OH)₂/C, Pd(OAc)₂polyurea microcapsules (NP Pd(0) Encat™ 30), Au/TiO₂, Rh/C, Ru/Al₂O₃,Ir/CaCO₃, and Pt/C, or a mixture thereof. NP Pd(0) Encat™ 30 isPalladium(0), microencapsulated in polyurea matrix, and is availablefrom Sigma Aldrich as Product Number 653667.

More particularly, the hydrogenation catalyst is selected from the groupconsisting of a Raney catalyst, Pd/C, Pd(OH)₂/C, Au/TiO₂, Rh/C,Ru/Al₂O₃, Ir/CaCO₃, and Pt/C, or a mixture thereof. More particularly,the hydrogenation catalyst is Pd/C, Pd(OH)₂/C, Au/TiO₂, Rh/C, Ra—Ni, orPt/C. Most particularly, the hydrogenation catalyst is Pd/C or Ra—Ni.Palladium is used in catalytic amounts, e.g. 0.001 to 0.1 equivalents,preferably 0.01 to 0.1 equivalents, with respect to the compound offormula III.

The catalyst loading for the catalytic hydrogenolysis is typically 0.1to 20 weight percent. More typically, the catalyst loading for thecatalytic hydrogenolysis is typically 5 to 15 weight percent.

As indicated, the catalytic hydrogenolysis may be performed in thepresence of a suitable solvent. Suitable solvents include alcohols (e.g.methanol or ethanol), ethers (e.g. tetrahydrofuran, diisopropyl ether,t-butylmethyl ether, dibutyl ether, dimethyl acetal, or dioxane), ester(e.g. ethyl acetate), aromatic hydrocarbons (e.g. toluene ort-butyl-benzene), aliphatic hydrocarbons (e.g. hexanes, heptanes, orpentane), saturated alicyclic hydrocarbons (e.g. cyclohexane orcyclopentane), and aprotic polar solvents (e.g. dimethylformamide, ordimethyl sulfoxide) and a mineral or organic acid co-catalyst), usedalone or as a mixture. More particularly, the solvent is toluene, ethylacetate or tetrahydrofuran, or a mixture thereof, optionally in thepresence of water. In one particular embodiment, the solvent is amixture of tetrahydrofuran and ethyl acetate. In another particularembodiment, the solvent is toluene.

The catalytic hydrogenolysis is typically performed at a temperaturebetween 0 and 50° C. More typically, the deprotection is performed at atemperature between 10 and 40° C. In a particular embodiment, thetemperature is between 15 and 25° C.

Typically, the H₂ is added at a pressure of at least 0.1 bar, and morepreferably at a pressure between 0.1 to 100 bar. More particularly, theH₂ is added at a pressure between 0.2 bar to 30 bar, and moreparticularly, the H₂ is added at a pressure of 1 to 10 bar. In apreferred embodiment, the H₂ is added at a pressure of approximately 2bar.

In another embodiment, the present invention provides a process forpreparing a compound of formula III, comprising contacting a compound offormula IV with a compound of formula IV_(a).

The compound of formula IV_(a) (CASRN 157373-08-5) is generallyavailable from commercial sources or is readily prepared by a skilledartisan. For instance, the compound of formula IV_(a) can be preparedfrom the corresponding carboxylic acid (CASRN 61079-72-9) using thionylchloride or oxalyl chloride or the like in the presence of a catalystsuch as pyridine, dimethylformamide, triethyl amine, or diisopropylethylamine.

In another embodiment, the present invention provides a process forpreparing a compound of formula III, comprising contacting a compound offormula IV with a compound of formula IV_(a) in the presence of a base.

In a particular embodiment of the invention, the base is an inorganicbase, which is preferably an alkali or alkali earth metal hydroxide,phosphate, or carbonate. More particularly, the inorganic base isselected from the group consisting of LiOH, NaOH, KOH, CsOH, NH₄OH,RbOH, Mg(OH)₂, Ca(OH)₂, Ba(OH)₂, Li₂CO₃, Na₂CO₃, K₂CO₃, Cs₂CO₃,(NH₄)₂CO₃, and K₃PO₄. In a particular embodiment, the base is K₃PO₄,K₂CO₃, or KOH. In a more particular embodiment, the base is K₃PO₄,K₂CO₃, or KOH. The base is typically used as a mixture in water.

In one embodiment, the reaction is accomplished in a suitable solvent inthe presence of the base. In one embodiment, the solvent is selectedfrom the group consisting of an ether (e.g. tetrahydrofuran, diisopropylether, t-butylmethyl ether, dibutyl ether, dimethyl acetal, or dioxane,2-MeTHF); an alcohol such as methanol or ethanol or the like; toluene;or a mixture thereof. In one particular embodiment, the solvent istoluene. In another particular embodiment, the solvent is a mixture oftetrahydrofuran and water. The reaction is typically performed at atemperature of approximately 10 to 20° C.

In another embodiment, the present invention provides a process forpreparing a compound of formula IV_(a), comprising reacting a compoundof formula IV_(b) with oxalyl chloride, thionyl chloride, or the like,in the presence of a catalyst such as pyridine, dimethylformamide,triethyl amine, or diisopropylethyl amine.

In a particular embodiment, the conversion of compound IV_(b) to N_(a)is carried out in the presence of pyridine or dimethylformamide,particularly in the presence of trace amount of pyridine, moreparticularly wherein between about 0.001 and 0.02 eq of pyridine isbeing used, most particularly wherein about 0.005 eq of pyridine isbeing used.

In another embodiment, the present invention provides a process forpreparing a compound of formula IV, comprising deprotecting a compoundof formula V,

wherein PG is an amino protecting group. In one embodiment, the aminoprotecting group is an FMoc, CBz, or BOC protecting group. In aparticular embodiment, the amino protecting group is a BOC protectinggroup.

The deprotection of a compound of formula V may be performed in thepresence of a solvent, such as an alcohol (e.g. methanol or ethanol), anether-like solvent (e.g. tetrahydrofuran, diisopropyl ether,t-butylmethyl ether, dibutyl ether, dimethyl acetal, or dioxane),ester-like solvent (e.g. ethyl acetate), aromatic solvent (e.g. tolueneor t-butyl-benzene), an aliphatic hydrocarbon solvent (e.g. hexanes,heptanes, or pentane), a saturated alicyclic hydrocarbon solvent (e.g.cyclohexane or cyclopentane), an aprotic polar solvents (e.g.dimethylformamide), or dimethyl sulfoxide and a mineral or organicco-catalyst, preferably in the presence of methanol, ethanol,isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran,toluene, or dimethylformamide and hydrochloric acid or acetic acid.

In a particular embodiment, the deprotection is carried out in a solventin the presence of a strong mineral or organic acid, particularlytrifluoroacetic acid, methansulfonic acid, p-toleunensulfonic acid,Lewis acids, particularly trialkylsilyl iodides, trimethylsilyl halides,boron trifuoride diethyl etherate, zinc halides, tin halides, or aninorganic acid. More particularly the acid is sulfuric acid, HBr, orHCl. Common conditions include HCl/dioxane, trifluoroaceticacid/methylene chloride. In one embodiment the deprotection is carriedout in a heterogeneous mixture containing aqueous HCl and toluene.

In another embodiment, the present invention provides a process forpreparing a compound of formula V wherein PG is an amino protectinggroup, comprising reducing a compound of formula VI.

In one embodiment, the reaction occurs in the presence of a reducingagent. The reducing agent can be selected from the group consisting ofborohydrides. In particular, the reducing agent is selected from thegroup consisting of NaBH₄, NaBH(OAc)₃, and NaBH₃CN. More preferably, thereducing agent is NaBH₃CN or NaBH₄ and LiCN, NaCN, or KCN underconditions used in typical reductive amination procedures. A typicalreductive amination procedure involves combining an amine and a carbonylcompound in the presence of a complex metal hydride such as NaBH₄,LiBH₄, NaBH₃CN, Zn(BH₄)₂, sodium triacetoxyborohydride, orborane/pyridine under mild acidic conditions, conveniently at a pH of1-5, which promotes formation of the intermediate iminium salt which isthen reduced by the metal hydride. More preferably, the reducing agentis NaBH₃CN.

The preparation of a compound of formula V may be performed in thepresence of a solvent, such as an alcohol solvent (e.g. methanol orethanol), an ether-like solvent (e.g. tetrahydrofuran, diisopropylether, t-butylmethyl ether, dibutyl ether, dimethyl acetal, or dioxane),ester-like solvent (e.g. ethyl acetate), aromatic solvent (e.g. tolueneor t-butyl-benzene), an aliphatic hydrocarbon solvent (e.g. hexanes,heptanes, or pentane), a saturated alicyclic hydrocarbon solvent (e.g.cyclohexane or cyclopentane), an aprotic polar solvents (e.g.dimethylformamide), or dimethyl sulfoxide and a mineral or organicco-catalyst, preferably in the presence of methanol, ethanol,isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran,toluene, or dimethylformamide.

In another embodiment, the present invention provides a process forpreparing a compound of formula VI comprising reacting a compound offormula VII (CASRN 106565-71-3) with a compound of formula VII_(a),

wherein PG is an amino protecting group such as Fmoc, Cbz, or Boc or thelike. The compound of formula VII_(a) is generally available fromcommercial sources or is readily prepared using methods well known tothe person skilled in the art. (See, for example, Rice, K. et al. Med.Chem. Lett. 2012, 3, 416, and Podlech, J. and Seebach, D. Helv. Chim.Acta 1995, 1238.) For example, the compound of formula VII_(a) whereinPG is Boc is commercially available from Sigma Aldrich as1-Boc-azetidinone (tert-butyl 3-oxo-1-azetidinecarboxylate, CASRN398489-26-4). Similarly, the compound of formula VII is generallyavailable from commercial sources or is readily prepared using methodswell known to the person skilled in the art. (See, for example, N. R.Guz et al., Org. Proc. Res. Develop. 2010 14(6):1476). For example, thecompound of formula VII is commercially available, from Sigma Aldrich,as (3S,5R,8aS)-3-phenyl-hexahydro-oxazolo[3,2-a]pyridine-carbonitrile(CAS Reg. No. 106565-71-3).

In one embodiment, the reaction is accomplished in a suitable solvent inthe presence of a base. In one embodiment, the solvent is a polaraprotic solvent selected from ethers such as tetrahydrofuran,diisopropyl ether, t-butylmethyl ether, dibutyl ether, dimethyl acetal,dioxane, or 2-MeTHF or mixtures thereof, used alone or in combinationwith a polar aprotic solvent such as1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). In aparticular embodiment, the solvent is THF used in combination with DMPU.

In this and other embodiments, the base is an amine base such as thelithium, sodium, or potassium salts of mono or bis substituted alkyl oraromatic amines, and silylalkyl or silylaromatic amines. In a particularembodiment, the strong base is selected from the group consisting of thelithium, sodium, or potassium salts of diisopropyl amine,bis(trimethylsilyl)amine, diethylamine, and dimethylamine. In anotherembodiment, the strong base is selected from the group consisting of thelithium, sodium, and potassium salts of bis(trimethylsilyl)amine. Moreparticularly, the strong base is selected from the group consisting oflithium diisopropylamide, lithium bis(trimethylsilyl)amide, and lithiumdiethylamide. More particularly, the base is lithium diisopropylamide.

The reaction is typically performed at low temperature. In oneembodiment, the reaction temperature is about 0 to −80° C. In anotherembodiment, the reaction temperature is about −20 to −80° C. In a morepreferable embodiment, the reaction temperature is about −50 to −80° C.In another preferable embodiment, the reaction temperature is about −70to −80° C.

In another embodiment, the present invention provides a process forpreparing a compound of formula V, comprising the following steps:

1) reacting a compound of formula VII with a compound of formula VII_(a)as previously described to provide a compound of formula VI;

and

-   -   2) reducing a compound of formula VI with a reducing agent as        previously described to provide a compound of formula V.

In one embodiment, steps 1 to 2 steps can be telescoped.

In another embodiment, the present invention provides a process for thepreparation of the compound of formula IV, which comprises the followingsteps:

1) reacting a compound of formula VII with a compound of formula VII_(a)as previously described to provide a compound of formula VI;

2) reducing a compound of formula VI with a reducing agent as previouslydescribed to provide a compound of formula V;

and

3) deprotecting the azetidinyl ring of a compound of formula V aspreviously described to provide a compound of formula IV.

In particular, any combination of steps 1 to 3 or all steps can betelescoped. More particularly steps 2 and 3 are telescoped.

In another embodiment, the present invention provides a process for thepreparation of the compound of formula III, which comprises thefollowing steps:

1) reacting a compound of formula VII with a compound of formula VII_(a)as previously described to provide a compound of formula VI;

2) reducing a compound of formula VI with a reducing agent as previouslydescribed to provide a compound of formula V;

3) deprotecting the azetidinyl ring of a compound of formula V aspreviously described to provide a compound of formula IV;

and;

4) reacting a compound of formula IV with a compound of formula IV_(a),as previously described to provide a compound of formula III.

In particular, any combination of steps 1 to 4 or all steps can betelescoped. More particularly steps 2 to 4 are telescoped.

In another embodiment, the present invention provides a process for thepreparation of the compound of formula II, which comprises the followingsteps:

1) reacting a compound of formula VII with a compound of formula VII_(a)as previously described;

2) reducing a compound of formula VI with a reducing agent as previouslydescribed, to provide a compound of formula V;

3) deprotecting the azetidinyl ring of a compound of formula V aspreviously described to provide a compound of formula IV;

4) reacting a compound of formula IV with a compound of formula IV_(a)as previously described to provide a compound of formula III;

and

5) hydrogenation of a compound of formula III, as previously describedto provide a compound of formula II.

Any combination of steps 1 to 5 or all steps can be telescoped. Moreparticularly steps 2 to 5 are telescoped.

In another embodiment, the present invention provides a process for thepreparation of a compound of formula I′, which comprises the followingsteps:

1) reacting a compound of formula VII with a compound of formula VII_(a)as previously described to provide a compound of formula VI;

2) reducing a compound of formula VI with a reducing agent as previouslydescribed to provide a compound of formula V;

3) deprotecting the azetidinyl ring of a compound of formula V aspreviously described to provide a compound of formula IV;

4) reacting a compound of formula IV with a compound of formula IV_(a)as previously described to provide a compound of formula III;

5) hydrogenation of a compound of formula III as previously described toprovide a compound of formula II;

and

6) reacting a compound of formula II with a compound of formula IL aspreviously described to provide a compound of formula I′.

In particular, any combination of steps 1 to 6 or all steps can betelescoped. More particularly, steps 2 to 5 are telescoped.

In another embodiment, the present invention provides a process for thepreparation of the compound of formula I′, which comprises the followingsteps:

(a) hydrogenation of a compound of formula III as previously describedto provide a compound of formula II;

and

(b) reacting a compound of formula II with a compound of formula II_(a)as previously described to provide a compound of formula I.

In particular, steps (a) and (b) can be telescoped.

In another embodiment, the present invention provides a process for thepreparation of the compound of formula I′, which comprises the followingsteps:

(a) reacting a compound of formula IV with a compound of formula Na aspreviously described to provide a compound of formula III;

(b) hydrogenation of a compound of formula III, as previously describedto provide a compound of formula II;

and

(c) reacting a compound of formula II with a compound of formula II_(a)as previously described to provide a compound of formula I′.

In particular, any combination of steps (a) to (c) or all steps can betelescoped. More particularly steps (a) and (b) are telescoped.

In another embodiment, the present invention provides a process for thepreparation of the compound of formula I′, which comprises the followingsteps:

(a) deprotecting the azetidinyl ring of a compound of formula V aspreviously described to provide a compound of formula IV;

(b) reacting a compound of formula IV with a compound of formula IV_(a)as previously described to provide a compound of formula III;

(c) hydrogenation of a compound of formula III as previously describedto provide a compound of formula II;

and

(d) reacting a compound of formula II with a compound of formula II_(a)as previously described to provide a compound of formula I′.

In particular, any combination of steps a) to d) or all steps can betelescoped. More particularly steps (a) and (c) are telescoped.

In another embodiment, the present invention provides a process for thepreparation of the compound of formula I′, which comprises the followingsteps:

a) reacting a compound of formula VI with a reducing agent, aspreviously described;

b) deprotecting the azetidinyl ring of a compound of formula V, aspreviously described;

c) reacting a compound of formula IV with a compound of formula IV_(a),as previously described;

d) hydrogenation of a compound of formula III, as previously described;

and

-   -   e) reacting a compound of formula II with a compound of formula        II_(a), as previously described to provide a compound of formula        I′.

In particular, any combination of steps (a) to (e) or all steps can betelescoped. More particularly steps (a) to (d) are telescoped.

In a further embodiment the present invention provides a process for thepreparation of a compound of formula I obtained by any of the processesand conditions mentioned previously.

A further aspect of the present invention provides a compound of formulaVI;

wherein PG is an amino protecting group. In one embodiment, PG istert-butyloxycarbonyl (Boc).

A further aspect of the present invention provides a compound of formulaV:

wherein PG is an amino protecting group. In one embodiment, PG istert-butyloxycarbonyl (Boc).

A further aspect of the present invention provides a compound of formulaIV.

A further aspect of the present invention provides a compound of formulaIII.

A further aspect of the present invention provides a compound of formulaII.

Additional Embodiments

The present invention also includes the following additionalembodiments.

Embodiment 1

A process for making a compound of formula I:

wherein:

A is arylene or heteroarylene optionally substituted with one, two,three, or four groups selected from R⁶, R⁷, R⁸, and R⁹, each of whichare independently selected from hydrogen, halo, (C₁-C₈)alkyl,halo(C₁-C₈)alkyl, hydroxy, (C₁-C₆)alkoxy, and halo(C₁-C₆)alkoxy;

X is alkyl, halo, halo(C₁-C₈)alkyl, or halo(C₁-C₆)alkoxy;

R¹, R², R³, and R⁴ are each independently hydrogen, (C₁-C₈)alkyl, orhalo(C₁-C₈)alkyl;

R⁵ is hydrogen, halo, or (C₁-C₈)alkyl; comprising:

contacting a compound of formula II-1 wherein X and R⁵ are as definedabove and a compound of formula II_(a)-1 wherein R¹⁰ is F, Br, Cl, or—OSO₂—CF₃ and R¹¹ is H or a protecting group in the presence of a strongbase to provide a compound of formula I.

Embodiment 2

The process of any one of embodiments 1 or 2, wherein X and R⁵ in acompound of formula II_(a)-1 are each independently F, Cl, Br, or I.

Embodiment 3

The process of any one of embodiments 1 to 3, wherein X is F and R⁵ isI.

Embodiment 4

The process of any one of embodiments 1 to 3 wherein the compound offormula II-1 is the compound of formula II-2,

wherein R¹¹ is H or protecting group and Ring A is optionallysubstituted with one, two, three or four groups selected from R⁶, R⁷,R⁸, and R⁹, each of which are independently selected from halo,(C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₁-C₆)alkoxy, and halo(C₁-C₆)alkoxy.

Embodiment 5

The process of any one of embodiments 1 to 4, wherein the compound offormula II-1 is the compound of formula II-3,

wherein R¹¹ is as defined previously; R¹⁰ is F, Cl, Br, I, or OSO₂CF₃;and R^(12a) and R^(12b) are each independently F, Cl, Br, I, alkyl,haloalkyl, alkoxy, or haloalkoxy.

Embodiment 6

The process of embodiment 5, wherein R¹⁰ in the compound of formula II-3is F, Cl, Br, or I, and R^(12a) and R^(12b) are each independently F,Cl, Br, alkyl, haloalkyl, alkoxy, or haloalkoxy.

Embodiment 7

The process of any one of embodiments 1 to 6, wherein R¹⁰ in thecompound of formula II-3 is F and R^(12a) and R^(12b) are eachindependently F, Cl, alkyl, or alkoxy.

Embodiment 8

The process of any of embodiments 1-7 wherein the strong base isselected from the group consisting of butyllithium, t-butyllithium, thelithium, sodium, or potassium salts of mono or bis-substituted alkyl oraromatic amines, and silylalkyl or silylaromatic amines.

Embodiment 9

The process of any of embodiments 1-8, wherein the strong base isselected from the group consisting of the lithium, sodium, or potassiumsalts of diisopropyl amine, bis(trimethylsilyl)amine, diethylamine, anddimethylamine.

Embodiment 10

The process of any one of embodiments 1 to 9, wherein the strong base islithium bis(trimethylsilyl)amide.

Embodiment 11

The process of any one of embodiments 1 to 10, wherein reaction isperformed in the presence of a solvent which is tetrahydrofuran.

Embodiment 12

The process of any of embodiments 1 to 11, wherein the compound offormula II_(a)-1 is a compound of formula II_(a); the compound offormula II-1 is a compound of formula I; and the compound of formula Iis a compound of formula I′.

Embodiment 13

A process for preparing a compound of formula II, comprisingdeprotecting a compound of formula III,

wherein deprotection comprises hydrogenation using H₂ in the presence ofa heterogeneous transition metal hydrogenation catalyst or treatmentwith chloroethyl chloroformate in the presence of MeCN or Na/NH₃.

Embodiment 14

The process of embodiment 13, wherein the heterogeneous transition metalhydrogenation catalyst is selected from the group consisting of a Raneycatalyst, Pd/C, Pd(OH)₂/C, Pd(OAc)₂, Au/TiO₂, Rh/C, Ru/Al₂O₃, Ir/CaCO₃,Pt/C, and Palladium(0) microencapsulated in polyurea matrix as a 45percent mixture of nanoparticles of palladium approximately 2 nm in sizein water, containing 0.4 mmol/g Pd(0) (dry basis), where the unit weightincludes the weight of water (NP Pd(0) Encat™ 30), or a mixture thereof.

Embodiment 15

The process of embodiment 14, wherein the heterogeneous transition metalhydrogenation catalyst is Pd/C.

Embodiment 16

A process for preparing a compound of formula III, comprising contactinga compound of formula IV_(a) with a compound of formula IV.

Embodiment 17

The process of embodiment 16 in the presence of an inorganic base whichis an alkali or alkali earth metal hydroxide, phosphate, or carbonate.

Embodiment 18

The process of any one of embodiments embodiment 16 to 17, wherein theinorganic base is selected from the group consisting of LiOH, NaOH, KOH,CsOH, NH₄OH, RbOH, Mg(OH)₂, Ca(OH)₂, Ba(OH)₂, Li₂CO₃, Na₂CO₃, K₂CO₃,Cs₂CO₃, (NH₄)₂CO₃, and K₃PO₄.

Embodiment 19

The process of any one of embodiments 16 to 18, wherein the inorganicbase is K₃PO₄, K₂CO₃, or KOH.

Embodiment 20

A process for preparing a compound of formula IV, comprisingdeprotecting a compound of formula V:

wherein PG is an amino protecting group selected from the groupconsisting of FMoc, CBz, or BOC protecting group.

Embodiment 21

The process of embodiment 20, wherein the protecting group is a BOCprotecting group.

Embodiment 22

A process for preparing a compound of formula V wherein PG is an aminoprotecting group, comprising reducing a compound of formula VI with areducing agent selected from the group consisting of borohydrides.

Embodiment 23

A process for preparing a compound of formula VI comprising reacting acompound of formula VII with a compound of formula VII_(a) in thepresence of base wherein PG is an amino protecting group.

Embodiment 24

A process for the preparation of the compound of formula I′

which comprises the following steps:

1) reacting a compound of formula VII with a compound of formula VII_(a)to provide a compound of formula VI;

2) reducing a compound of formula VI with a reducing agent selected fromthe group consisting of borohydrides to provide a compound of formula V:

3) deprotecting the azetidinyl ring of a compound of formula V toprovide a compound of formula IV;

4) reacting a compound of formula IV with a compound of formula IV_(a)to provide a compound of formula III;

5) hydrogenation of a compound of formula III to provide a compound offormula II;

and

6) reacting a compound of formula II with a compound of formula II_(a)to provide a compound of formula III.

Embodiment 25

A process for the preparation of the compound of formula I′ whichcomprises contacting a compound of formula II and compound of formulaII_(a) in the presence of a strong base to provide a compound of formulaI′.

Embodiment 26

The process of embodiment 25, further comprising the step ofhydrogenation of a compound of formula III to provide a compound offormula II.

Embodiment 27

The process of embodiment 26, further comprising the step of reacting acompound of formula IV with a compound of formula IV_(a) to provide acompound of formula III.

Embodiment 28

The process of embodiment 27, further comprising the step ofdeprotecting the azetidinyl ring of a compound of formula V.

Embodiment 29

The process of embodiment 28, further comprising reducing a compound offormula VI with a reducing agent selected from the group consisting ofborohydrides to provide a compound of formula V.

Embodiment 30

The process of embodiment 29, further comprising reacting a compound offormula VII with a compound of formula VII_(a) in the presence of base.

Embodiment 31

A compound which is:

wherein PG is a protecting group;

wherein PG is an amino protecting group;

or

Embodiment 32

The compound of embodiment 31, wherein PG in the compound of formulas VIand V is BOC.

Synthesis

Compounds of this invention can be made by the synthetic proceduresdescribed below. The starting materials and reagents used in preparingthese compounds are either available from commercial suppliers such asSigma Aldrich Chemical Co. (Milwaukee, Wis.), or Bachem (Torrance,Calif.), or are prepared by methods known to those skilled in the artfollowing procedures set forth in references such as Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced OrganicChemistry, (John Wiley and Sons, 4^(th) Edition) and Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989). Theseschemes are merely illustrative of some methods by which the compoundsof this invention can be synthesized, and various modifications to theseschemes can be made and will be suggested to one skilled in the arthaving referred to this disclosure. The starting materials and theintermediates of the reaction may be isolated and purified if desiredusing conventional techniques, including but not limited to filtration,distillation, crystallization, chromatography, and the like. Suchmaterials may be characterized using conventional means, includingphysical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure and over a temperature range from about−78° C. to about 150° C., more preferably from about 0° C. to about 125°C., and most preferably at about room (or ambient) temperature, e.g.,about 20° C. Unless otherwise stated (as in the case of ahydrogenation), all reactions are performed under an atmosphere ofnitrogen.

The compounds disclosed and claimed herein have asymmetric carbon atomsor quaternized nitrogen atoms in their structure and may be preparedthrough the through syntheses described herein as single stereoisomers,racemates, and as mixtures of enantiomers and diastereomers. Thecompounds may also exist as geometric isomers. All such singlestereoisomers, racemates, and mixtures thereof, and geometric isomersare intended to be within the scope of this invention.

Some of the compounds of the invention may exist as tautomers. Forexample, where a ketone or aldehyde is present, the molecule may existin the enol form; where an amide is present, the molecule may exist asthe imidic acid; and where an enamine is present, the molecule may existas an imine. All such tautomers are within the scope of the invention.

Methods for the preparation and/or separation and isolation of singlestereoisomers from racemic mixtures or non-racemic mixtures ofstereoisomers are well known in the art. For example, optically active(R)- and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. Enantiomers (R- andS-isomers) may be resolved by methods known to one of ordinary skill inthe art, for example by: formation of diastereomeric salts or complexeswhich may be separated, for example, by crystallization; via formationof diastereomeric derivatives which may be separated, for example, bycrystallization; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic oxidation orreduction, followed by separation of the modified and unmodifiedenantiomers; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where a desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step may be required to liberate the desired enantiomeric form.Alternatively, specific enantiomers may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents or by converting on enantiomer to the other by asymmetrictransformation. For a mixture of enantiomers, enriched in a particularenantiomer, the major component enantiomer may be further enriched (withconcomitant loss in yield) by recrystallization.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The methods of the present invention may be carried out assemi-continuous or continuous processes, more preferably as continuousprocesses.

The present invention as described above unless indicated otherwise maybe carried out in the presence of a solvent or a mixture of two or moresolvents. In particular the solvent is an aqueous or an organic solventsuch as the ether-like solvent (e.g. tetrahydrofuran,methyltetrahydrofuran, diisopropyl ether, t-butylmethyl ether or dibutylether)aliphatic hydrocarbon solvent (e.g. hexane, heptane or pentane),saturated alicyclic hydrocarbon solvent (e.g. cyclohexane orcyclopentane) or aromatic solvent (e.g. toluene, o- m- or p-xylene ort-butyl-benzene) or mixture thereof.

The starting materials and reagents, which do not have their syntheticroute explicitly disclosed herein, are generally available fromcommercial sources or are readily prepared using methods well known tothe person skilled in the art.

In general, the nomenclature used in this Application is based onAUTONOM™ 2000, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. Chemical structures shownherein were prepared using MDL ISIS™ version 2.5 SPS. Any open valencyappearing on a carbon, oxygen or nitrogen atom in the structures hereinindicates the presence of a hydrogen atom.

Compounds of formula I, particularly the compound of formula I′, can beprepared as generally depicted in Scheme 1. Reaction of commerciallyavailable(3S,5R,8aS)-3-phenyl-hexahydro-oxazolo[3,2-a]pyridine-carbonitrileVII_(a) with commercially availabletert-butyl-3-oxo-1-azetidinecarboxylate VII in the presence of baseprovides compound VI. Compound VI is treated with a hydride reducingagent such as sodium cyanoborohydride in the presence of acid, followedby treatment with aqueous sodium hydroxide, to provide compound V.Deprotection of V using acid gives compound IV, which is coupled to acidchloride IV_(a) in the presence of a catalytic amount of pyridine toprovide III. Hydrogenation of III provided piperidine derivative II.Finally, coupling of II with 2-fluoro-4-iodo aniline Ha provides thedesired compound.

The following examples are provided for the purpose of furtherillustration and are not intended to limit the scope of the claimedinvention.

Example 1 Synthesis of3-((3S,5R,8aS)-5-Cyano-3-phenyl-hexahydro-oxazolo[3,2-a]pyridin-5-yl)-3-hydroxy-azetidine-1-carboxylicacid tert-butyl ester

A mixture of(3S,5R,8aS)-3-phenyl-hexahydro-oxazolo[3,2-a]pyridine-carbonitrile (20.0g, 87.6 mmol, 1.0 eq.) and dimethyltetrahydropyrimidone (DMPU, 11.3 g,87.6 mmol, 1.0 eq.) in THF (95.1 mL) was stirred for 10 min until aclear solution was observed. The mixture was then cooled to −70 to −80°C. and lithium diisopropylamide (28% soln. in heptane, THF andethylbenzene) (35.2 g, 92 mmol, 1.05 eq.) was added over 30 min whilemaintaining the internal temperature between −70 to −80° C. Aftercomplete addition, the mixture was stirred at −70 to −80° C. for anadditional 2 h, followed by dosing a solution of3-oxo-azetidine-1-carboxylic acid tert-butyl ester (16.2 g, 94.6 mmol,1.08 eq.) in THF (16.4 g) over 30 min while maintaining the internaltemperature between −70 to −80° C. After complete dosage, the reactionmixture was stirred at −70 to −80° c. for 1 h.

In a separate flask, a solution of sodium chloride (10.3 g), deionizedwater (103.0 g) and acetic acid (5.29 g, 87.6 mmol, 1.0 eq.) wasprepared and cooled to 0° C. The reaction mixture was dosed onto thequench mixture over 30 min while maintaining the internal temperature atless than 10° C. The flask of the reaction mixture was rinsed with THF(26.7 g) and the rinse was combined with the quenched mixture. Aftervigorously stirring for 20 min at 5° C., agitation was stopped and thelayers were allowed to separate. The lower aqueous phase was discarded.Ethyl acetate (61.8 g) and deionized water (68.5 g) were added to theorganic phase. After vigorously stirring at 5° C. for 10 min, agitationwas stopped, the layers were allowed to separate, and the lower aqueousphase was discarded. The washing procedure was repeated once withdeionized water (68.5 g).

The organic phase was concentrated under reduced pressure (jackettemperature approximately 40-45° C., pressure=200-180 mbar) until atotal volume of approximately 120 mL of distillate was collectedresulting in a yellowish solution. The vacuum was released and heptane(102.0 g) was added over 10 min. Distillation under reduced pressure wascontinued (jacket temperature approximately 35-40° C., pressureapproximately 250-110 mbar) by adding heptane (177 g) at a rate so thatthe residual volume was kept constant. After 10 min of distilling, athick, stirrable suspension was obtained. The vacuum was released andisopropanol (10.2 g) was added over 15 min at 35° C. The suspension washeated at 45° C. and stirred for 30 min. Thereafter, the suspension wascooled to 0° C. over 2 h and held at 0° C. for 1 h. The suspension wasfiltered over a glass filter. The flask and filter cake were rinsed withpre-cooled (approximately 5° C.) heptane (46.6 g), and the wet cake wasdried overnight at 40° C. under reduced pressure until constant weightto yield the title compound as slightly beige crystals. HPLC purity:91.9%-area. Mp. (DSC): extrapolated peak: 151.80° C. ¹H-NMR (600 MHz,CDCl₃): δ 7.30-7.50 (m, 5H), 4.17-4.27 (m, 3H), 3.94-4.01 (m, 2H),4.11-4.1 (m, 2H), 4.09 (d, 1H), 3.95 (d, 1H), 3.87 (dd, 1H), 3.76 (dd,1H), 3.54-3.70 (br, 1H), 2.85-3.03 (br, 1H), 2.18-2.25 (m, 1H), 2.12(br, 1H), 1.97-2.04 (m, 1H), 1.85-1.94 (m, 1H), 1.61-1.79 (m, 3H), 1.41(s, 9H). MS (EI): m/z=400.48 ([M+H]⁺, 100%).

Example 2 Synthesis of3-Hydroxy-3-[(S)-1-((S)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-yl]azetidine-1-carboxylicacid tert-butyl ester

A mixture of3-((3S,5R,8aS)-5-cyano-3-phenyl-hexahydro-oxazolo[3,2-a]pyridin-5-yl)-3-hydroxy-azetidine-1-carboxylicacid tert-butyl ester (12.0 g, 30.0 mmol, 1.0 eq.) and sodiumcyanoborohydride (3.18 g, 50.6 mmol, 1.68 eq.) in EtOH (70 mL) washeated to 30° C. and slowly added within two h to a warm mixture (70°C.) of acetic acid (3.63 ml, 63.5 mmol, 2.1 eq.) in EtOH (20 mL). Theresulting mixture was subsequently stirred for another 3 h at 70 to 75°C. After complete reaction, the mixture was cooled to 23° C. and slowlydosed within 30 min into a mixture of toluene (100 mL) and aqueous NaOH(60 g, 10%-w/w) and stirred for 15 min. The reaction flask was rinsedwith the quenched mixture. The layers were separated, and the organicphase was washed with toluene (30 mL). The combined organic phases wereconcentrated under vacuum (200 to 85 mbar at 35 to 40° C. jackettemperature) until 80 mL (70.82 g) of a yellowish product solution wasobtained. HPLC purity: 97.6% area.

For analytical purposes, the product solution was fully concentrated inthe rotary evaporator, treated with EtOH and again fully concentratedresulting in 19.2 g of a foamy product. The residue was dissolved in amixture of ethyl acetate (30 mL) and MeOH (15 mL) and purified by flashchromatography over 120 g silica gel using ethyl acetate as eluent.Fractions 3 to 5 of 6 fractions of 100 mL each were combined and fullyconcentrated under vacuum in the rotary evaporator resulting in 14.6 gof colorless foam. This residue was again dissolved in a minimum of amixture of heptane/ethyl acetate 2:1 (v/v) and purified by flashchromatography over 190 g of silica gel using heptane/ethyl acetate 2:1(v/v) as eluent. After a forerun of 700 mL, ten subsequent fractions(800 mL total) were combined, fully evaporated in the rotary evaporatorunder vacuum (bath temperature 35° C., pressure ≥20 mbar) and theresidue was dried overnight at 35° C. and under vacuum until constantweight to yield the title compound as a colorless solid. Mp. (DSC):extrapolated peak: 220.9° C. (melting accompanied by exothermicdecomposition). ¹H-NMR (600 MHz, CDCl₃): δ 7.38-7.41 (m, 2H), 7.34-7.38(m, 2H), 7.27-7.30 (m, 1H), 4.28-4.50 (br, 1H), 4.19 (dd, 1H), 4.11-4.1(m, 2H), 4.09 (d, 1H), 3.95 (d, 1H), 3.87 (dd, 1H), 3.83 (t, 1H),3.08-3.16 (m, 1H), 2.85 (ddd, 1H), 2.57 (ddd, 1H), 1.76-1.84 (m, 1H),1.68-1.75 (m, 1H), 1.53-1.58 (m, 1H), 1.41-1.48 (bs, 9H), 1.31-1.41 (m,2H), 1.21-1.31 (m, 2H). MS (EI): m/z=377.24 ([M+H]⁺, 100%). EA forC₂₁H₃₂N₂O₄: calcd: C, 66.99, H, 8.57, N, 7.44; found C, 67.38, H, 8.50,N, 7.29.

Example 3 Synthesis of3-[(S)-1-((S)-2-Hydroxy-1-phenyl-ethyl)-piperidin-2-yl]-azetidin-3-oldihydrochloride

A solution of3-hydroxy-3-[(S)-1-((S)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-yl]azetidine-1-carboxylicacid tert-butyl ester (69.8 g, 29.6 mmol, 1.0 eq.) in toluene wastreated at 23-27° C. within 12 min with a mixture of water (30.1 g) andHCl (37%, 7.22 g, 73.3 mmol, 2.5 eq.) and stirred for 10 min. Theresulting biphasic mixture was heated to 50° C. within 30 min and keptstirring for 4 h at 50° C. After complete conversion, the mixture wascooled down to room temperature and the phases were allowed to separate.The aqueous phase was washed with toluene (36 mL) and the phases wereallowed to separate, resulting in 44.2 g of a yellowish aqueous productsolution. HPLC purity: 96.3%-area.

For analytical purposes, the product solution was fully concentrated inthe rotary evaporator (bath temperature 45° C.). The yellow oily residuewas dissolved in MeOH (190 mL) and again fully concentrated in therotary evaporator and under vacuum. The residue was taken up in aminimum of a mixture of MeOH/ethyl acetate 1:1 (v/v) and purified byflash chromatography over silica gel (150 g) using a mixture ofMeOH/ethyl acetate 1:1 (v/v) as eluent. A forerun of 400 mL was takenand discarded and the subsequent fractions (1.5 L) were combined andcompletely concentrated in the rotary evaporator under vacuum (bathtemperature 40° C., pressure ≥20 mbar) resulting in a yellow oil thatwas dissolved in MeOH (20 mL). The oil was added drop-wise at roomtemperature to ethyl acetate (80 mL), whereupon the productprecipitated. The solids were filtered and rinsed with ethyl acetate (30mL). Drying overnight at 30° C. under vacuum until constant weightresulted in the title compound (22.0 g) as a colorless solid. Mp. (DSC):T_(onset) 114.2° C., extrapolated peak: 123.4° C. ¹H NMR (600 MHz,DMSO-do): δ 9.50-9.64 (br, 1H), 8.91-9.03 (br, 1H), 7.78 (s, 1H),7.62-7.56 (m, 2H), 7.41-7.52 (m, 3H), 6.03 (bs, 1H), 4.56-4.67 (m, 1H),4.45 (dd, 1H), 4.25-4.33 (m, 2H), 4.23 (dd, 1H), 4.18 (dd, 1H),3.95-4.05 (m, 1H), 3.83 (dd, 1H), 3.45-3.54 (m, 1H), 3.26-3.40 (m, 1H),1.67-1.86 (m, 4H), 1.55-1.65 (m, 1H), 1.37-1.51 (m, 1H). MS (EI):m/z=277 ([M+H]⁺ of free base 100%). EA for C₁₆H₂₆N₂O₂Cl₂, corrected forwater (9.2%-w/w) and HCl (2.1 eq. instead of 2.0 eq.): calcd: C, 49.44,H, 7.80, N, 7.21, O, 16.40, Cl, 19.15; found C, 48.76, H, 7.48, N, 7.36,O, 16.44, Cl, 19.11.

Example 4{3-Hydroxy-3-[(S)-1-((S)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-yl]-azetidin-1-yl}-(2,3,4-trifluoro-phenyl)-methanone

2,3,4-Trifluoro-benzoyl Chloride

2,3,4-Trifluorobenzoic acid (100 g, 568 mmol, 1.0 eq.) was suspended intoluene (1000 mL) and treated with pyridine (0.254 mL, 3.15 mmol, 0.0055eq.). The resulting suspension was heated to 60 to 70° C., whereupon themixture became a clear yellowish solution. At this temperature, oxalylchloride (94.4 g, 729 mmol, 1.3 eq.) was slowly added over 156 minutes.After complete addition, the mixture was kept stirring for 10 min untilcomplete. Toluene (360 mL) was partially removed by distillation undervacuum (jacket temperature: 60 to 70° C., pressure: 200 to 100 mbar).The solution was cooled to room temperature, resulting in 636 g of ayellowish and slightly turbid solution that was stored under N₂atmosphere and used in the subsequent step without any furthertreatment. HPLC purity: 99.2%-area.

{3-Hydroxy-3-[(S)-1-((S)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-yl]-azetidin-1-yl}-(2,3,4-trifluoro-phenyl)-methanone

The aqueous solution of3-[(S)-1-((S)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-yl]-azetidin-3-oldihydrochloride (43.5 g) was treated with EtOH (24 mL) and stirred for10 min at room temperature. To this mixture was added a solution oftripotassium phosphate (28.8 g, 136 mmol, 4.7 eq.) in 261 mL waterwithin 14 min at a batch temperature of 10 to 20° C. and the mixture wasstirred for 15 min at 15° C. (pH 11.9). To this solution was added viadropping funnel 34 g of the above described 2,3,4-Trifluoro-benzoylchloride solution (34.0 g, 29.8 mmol, 1.0 eq.) over 32 min at a batchtemperature of 10 to 20° C. while vigorously stirring. The droppingfunnel was rinsed with toluene (1.2 ml) and the biphasic mixture wasstirred at room temperature for 60 min. The layers were allowed toseparate, and the aqueous phase was discarded. The organic phase waswashed with a solution of sodium carbonate (3.36 g, 31.5 mmol, 1.09 eq.)in water (42 g) and stirred for 30 min at room temperature. The layerswere allowed to separate, and the organic phase was washed with aqueoussodium chloride (30 g, 10%-w/w). In the rotary evaporator (bathtemperature 50° C., pressure <200 mbar), the organic phase wasconcentrated to a volume of approximately 30%. The residue was taken upin EtOH (23 mL) and stirred for 5 min at 40 to 50° C. The solution wasagain concentrated in the rotary evaporator (bath temperature 50° C.,pressure less than 200 mbar, 17 ml distillate), resulting in a veryviscous oil. The residue was again taken up in EtOH (23 mL) and stirredfor 10 min and again further diluted with EtOH (12 mL) in order to reachthe target volume (53 mL, 46.06 g). HPLC purity: 85.0%-area.

For analytical purposes, the product solution (90 mL) was filtered andthe filter residue was washed with EtOH (15 ml). In the rotaryevaporator (bath temperature 40° C., pressure <150 mbar), the solutionwas completely concentrated, and the residue was taken up in MTBE (40mL), subsequently again fully concentrated, then taken up in a mixtureof ethyl acetate (29 mL) and heptane (40 mL), then fully concentrated,then again taken up in a mixture of MTBE (20 mL) and heptane (50 mL) andagain fully concentrated resulting, finally, in a foamy solid (32.5 g).The solid residue (32.0 g) was dissolved in ethyl acetate (20 mL) andpurified by flash chromatography over silica gel (150 g) using ethylacetate as eluent. After a forerun of 200 mL, 6 fractions (800 mL) werecombined and completely concentrated in the rotary evaporator (bathtemperature: 40° C., pressure ≥20 mbar) resulting in 28.0 g of aslightly yellowish oil. At room temperature, the oily residue was takenup in dichloromethane (20 mL), diluted with heptane (150 mL) and againfully concentrated in the rotary evaporator, followed by dissolving theresidue in MTBE (20 mL) and again by complete removal of the solvent inthe rotary evaporator resulting in a rubber-like foam. This foam wasdissolved in toluene (30 mL, room temperature) and dosed over 20 minadded drop-wise by dropping funnel at room temperature to heptane (400mL), whereupon the product started to precipitate. The dropping funnelwas rinsed with toluene (4 mL) and the suspension was kept stirring for1 h at room temperature. The solids were filtered off and the reactorand filter cake were twice rinsed with the filtrate and subsequentlywith heptane (15 mL). Drying under vacuum at 35° C. until weightconstancy resulted in 17.88 g of a colorless solid. HPLC purity:97.0%-area, residual solvents: toluene (1.2%-w/w) and heptane(2.3%-w/w). Mp (visually): T_(onset): 55-73° C. (melting accompanied byexothermic decomposition). ¹H NMR (400 MHz, DMSO-d₆, 120° C.): δ7.41-7.47 (m, 2H), 7.27-7.32 (m, 2H), 7.21-7.26 (m, 2H), 7.12-7.19 (m,1H), 5.21 (bs, 1H), 4.35 (bd, 1H), 4.22 (bs, 1H), 4.05 (dd, 1H),3.91-4.01 (m, 1H), 3.74-3.90 (m, 4H), 3.01 (dd, 1H), 2.75-2.84 (m, 1H),2.49-2.59 (m, 1H), 1.68-1.81 (m, 1H), 1.51-1.65 (m, 1H), 1.23-1.50 (m,3H), 1.09-1.22 (m, 1H). MS (EI): m/z=435 ([M+H]⁺, 100%). EA forC₂₃H₂₅F₃N₂O₃, corrected for residual toluene (1.2%-w/w) and heptane(2.3%-w/w): calcd: C, 64.38, H, 6.07, F, 12.66, N, 6.22; found C, 64.01,H, 6.04, F, 12.63, N, 6.35.

Example 5 Synthesis of((S)-3-Hydroxy-3-piperidin-2-yl-azetidin-1-yl)-(2,3,4-trifluoro-phenyl)-methanonehydrochloride

A 185 mL glass autoclave under argon was charged with Pd/C (3.37 g, 1.3mmol, 0.04 eq, 60.2% ww water, 10% ww Pd on C), water (0.22 g) and asolution of{3-hydroxy-3-[(S)-1-((S)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-yl]-azetidin-1-yl}-(2,3,4-trifluoro-phenyl)-methanonein EtOH (53 mL, 46 g, 29 mmol, 1.0 eq.). The mixture was treated withEtOH (13 mL), Acetic acid (4.15 mL, 72 mmol, 2.5 eq.) and with aqueoushydrochloric acid (2.5 ml, 37%-w/w, 30 mmol, 1.0 eq.). The autoclave wasrendered inert, pressurized with 2 bar of H₂, and the reaction was runat 2 bar H₂ pressure at 25° C. for 12 h. The pressure was released fromthe autoclave, and the suspension was treated with MeOH (25 mL) and keptstirring for 30 min and filtered under argon protection over filterpaper. The autoclave and the filter residue were rinsed with MeOH (4mL). The combined filtrates were evaporated under reduced pressure toapproximately 20-30 percent of the initial volume. The residue wastreated with isopropanol (38.5 mL) at 30 to 35° C., stirred for 1 h,cooled to 20 to 25° C., and treated with water (0.58 g) and with aqueoushydrochloric acid (2.5 mL, 37%-ww, 30 mmol, 1.0 eq.). The resultingsuspension was concentrated under vacuum at 25 to 35° C. until a volumeof approximately 22 mL was reached, and MTBE (31 mL) was added at 25 to35° C. The final suspension was cooled to 5 to 10° C., stirred for 1 h,and then filtered. The filter cake was rinsed with cold MTBE (12 mL) anddried under vacuum at 35° C. until weight constancy to yield the titlecompound (5.08 g) as a colorless solid. HPLC purity: 99.6%-area. Mp.(DSC): T_(onset): 246.3° C., extrapolated peak: 248.8° C. (meltingaccompanied by exothermic decomposition). ¹H NMR (400 MHz, DMSO-d₆, 120°C.): δ 8.59 (bs, 2H), 7.14-7.48 (m, 2H), 6.54 (bs, 1H), 4.39 (dd, 1H),4.23 (dd, 1H), 3.85-3.97 (m, 2H), 3.27-3.35 (m, 1H), 3.20-3.27 (m, 1H),2.80-2.95 (m, 1H), 1.78-1.88 (m, 2H), 1.64-1.78 (m, 2H), 1.40-1.64 (m,2H). MS (EI): m/z=315 ([M+H]⁺ of free base, 100%). EA forC₁₅H₁₇F₃N₂O₂×HCl: calcd: C, 51.36, H, 5.17, N, 7.99, F, 16.25; found C,51.19, H, 4.89, N, 7.91, F, 16.06.

Example 6 Synthesis of[3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-((S)-3-hydroxy-3-piperidin-2-yl-azetidin-1-yl)-methanone

To a solution of((S)-3-hydroxy-3-piperidin-2-yl-azetidin-1-yl)-(2,3,4-trifluoro-phenyl)-methanonehydrochloride (15.0 g, 42.8 mmol, 1.0 eq.) and 2-flouro-4-iodo-anilin(11.1 g, 47 mmol, 1.1 eq.) in THF (90 ml), a solution of LiHMDS in THF(149 g, 20.7% w/w, 184 mmol, 4.3 eq.) was dosed over 88 min at 20 to 30°C. Stirring was continued for 2 h. After complete conversion, themixture was dosed to a mixture of sulfuric acid (12.0 g, 96%-w/w, 118mmol, 2.75 eq.) in water (75 mL) over 25 min and kept stirring for 1 h.The layers were allowed to separate, and the organic phase was washedwith a mixture of water (60 mL) and toluene (96 mL). The organic phasewas concentrated under vacuum to a volume of approximately 150 mL.Toluene (250 mL) was added and residual THF was removed by distillationat 55° C. jacket temperature and at a pressure of 84 mbar while keepingthe batch volume constant by continuous dosing of toluene (400 mL),resulting in slow precipitation of the product. The batch temperaturewas then lowered to 10° C. within 2 h, and the suspension was keptstirring overnight at 10° C. The product was filtered off, and the cakewas rinsed with cold toluene (150 mL). Drying overnight under vacuum at35° C. until weight constancy yielded the title compound (20.66 g) as acolorless product. HPLC purity: 99.7%-area. M.p (DSC): T_(onset): 166.7°C., extrapolated peak: 168.2° C. (91.5 J/g). ¹H NMR (600 MHz, CDCl₃): δ8.28-8.48 (br, 1H), 7.39 (dd, 1H), 7.32 (ddd, 1H), 7.09-7.14 (m, 1H),6.75-6.86 (br, 1H), 6.60 (ddd, 1H), 4.10 (d, 2H), 4.05-4.20 (br, 1H),3.93-4.04 (br, 1H), 3.09 (d, 1H), 2.70 (d, 1H), 2.56-2.67 (br, 1H),1.68-1.87 (m, 1H), 1.50-1.64 (m, 2H), 1.25-1.38 (m, 2H), 1.07-1.24 (m,1H). MS (EI): m/z=532 ([M+H]⁺, 100%). EA for C₂₁H₂₁F₃IN₂O₃: calcd: C,47.47, H, 3.98, N, 7.91, F, 10.73; found C, 47.68, H, 4.00, N, 7.66, F,10.80.

Other Embodiments

The foregoing disclosure has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications can be made while remainingwithin the spirit and scope of the invention. It will be obvious to oneof skill in the art that changes and modifications can be practicedwithin the scope of the appended claims. Therefore, it is to beunderstood that the above description is intended to be illustrative andnot restrictive.

The scope of the invention should, therefore, be determined not withreference to the above description, but should instead be determinedwith reference to the following appended claims, along with the fullscope of equivalents to which such claims are entitled.

1. A process for making a compound of formula I:

wherein: A is arylene or heteroarylene optionally substituted with one, two, three, or four groups selected from R⁶, R⁷, R⁸, and R⁹, each of which are independently selected from hydrogen, halo, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, hydroxy, (C₁-C₆)alkoxy, and halo(C₁-C₆)alkoxy; X is alkyl, halo, halo(C₁-C₈)alkyl, or halo(C₁-C₆)alkoxy; R¹, R², R³, and R⁴ are each independently hydrogen, (C₁-C₈)alkyl, or halo(C₁-C₈)alkyl; R⁵ is hydrogen, halo, or (C₁-C₈)alkyl; comprising: contacting a compound of formula II-1 wherein X and R⁵ are as defined above with a compound of formula II_(a)-1 wherein R¹⁰ is F, Br, Cl, or —OSO₂—CF₃ and R¹¹ is H or a protecting group to provide a compound of formula I.


2. The process of any one of claim 1, wherein X and R⁵ in a compound of formula II_(a)-1 are each independently F, Cl, Br, or I.
 3. The process of any one of claims 1 or 2, wherein X is F and R⁵ is I.
 4. The process of any one of claims 1 to 3 wherein the compound of formula II-1 is the compound of formula II-2:

wherein R¹¹ is H or a protecting group and Ring A is optionally substituted with one, two, three or four groups selected from R⁶, R⁷, R⁸, and R⁹, each of which are independently selected from halo, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, (C₁-C₆)alkoxy, and halo(C₁-C₆)alkoxy.
 5. The process of any one of claims 1 to 4, wherein Ring A in the compound of formula II-2 is phenyl or pyridyl.
 6. The process of any one of claims 1 to 5, wherein the compound of formula II-1 is the compound of formula II-3:

wherein R¹¹ is as defined previously and R¹⁰ is F, Cl, Br, I, or OSO₂CF₃, and R^(12a) and R^(12b) are each independently F, Cl, Br, I, alkyl, haloalkyl, alkoxy, or haloalkoxy.
 7. The process of claim 6, wherein R¹⁰ in the compound of formula II-3 is F, Cl, Br, or I, and R^(12a) and R^(12b) are each independently F, Cl, Br, alkyl, haloalkyl, alkoxy, or haloalkoxy.
 8. The process of any one of claims 1 to 6, wherein R¹⁰ in the compound of formula II-3 is F and R^(12a) and R^(12b) are each independently F, Cl, alkyl, or alkoxy.
 9. A process for preparing a compound of formula I′, comprising contacting a compound of formula II_(a) with a compound of formula II.


10. The process of claim 9, further comprising a strong base.
 11. The process of claim 10, wherein the strong base is selected from the group consisting of butyllithium, t-butyllithium, the lithium, sodium, or potassium salts of mono or bis substituted alkyl or aromatic amines, and silylalkyl or silylaromatic amines.
 12. The process of any one of claim 10 or 11, wherein the strong base is selected from the group consisting of the lithium, sodium, or potassium salts of diisopropyl amine, bis(trimethylsilyl)amine, diethylamine, and dimethylamine.
 13. The process of any one of claims 10 to 12, wherein the strong base is selected from the group consisting of preferably the lithium, sodium, or potassium salts of bis(trimethylsilyl)amine.
 14. The process of any one of claims 10 to 13, wherein the strong base is selected from the group consisting of lithium diisopropylamide, lithium bis(trimethylsilyl)amide, or lithium diethylamide.
 15. The process of any one of claims 10 to 14, wherein the strong base is lithium bis(trimethylsilyl)amide.
 16. The process of any one of claims 10 to 15, wherein reaction is performed in the presence of a solvent which is tetrahydrofuran.
 17. A process for preparing a compound of formula II, comprising deprotecting a compound of formula III.


18. The process of claim 17, wherein deprotection comprises hydrogenation using H₂ in the presence of a heterogeneous transition metal hydrogenation catalyst or treatment with chloroethyl chloroformate in the presence of MeCN or Na/NH₃.
 19. The process of claim 18, wherein the heterogeneous transition metal hydrogenation catalyst is selected from the group consisting of a Raney catalyst, Pd/C, Pd(OH)₂/C, Pd(OAc)₂, Au/TiO₂, Rh/C, Ru/Al₂O₃, Ir/CaCO₃, Pt/C, and Palladium(0) microencapsulated in polyurea matrix as a 45 percent mixture of nanoparticles of palladium approximately 2 nm in size in water, containing 0.4 mmol/g Pd(0) (dry basis), where the unit weight includes the weight of water (NP Pd(0) Encat™ 30), or a mixture thereof.
 20. The process of claim 18 in the presence of HCl and acetic acid.
 21. The process of claims 17 to 20, wherein the heterogeneous transition metal hydrogenation catalyst is Pd/C.
 22. A process for preparing a compound of formula III, comprising contacting a compound of formula IV_(a) with a compound of formula IV.


23. The process of claim 22 in the presence of an inorganic base.
 24. The process of claim 22, wherein the inorganic base is an alkali or alkali earth metal hydroxide, phosphate, or carbonate.
 25. The process of any one of claims 22 to 24, wherein the inorganic base is selected from the group consisting LiOH, NaOH, KOH, CsOH, NH₄OH, RbOH, Mg(OH)₂, Ca(OH)₂, Ba(OH)₂, Li₂CO₃, Na₂CO₃, K₂CO₃, Cs₂CO₃, (NH₄)₂CO₃, and K₃PO₄.
 26. The process of any one of claims 22 to 25, wherein the inorganic base is K₃PO₄, K₂CO₃, or KOH.
 27. A process for preparing a compound of formula IV, comprising deprotecting a compound of formula V:

wherein PG is an amino protecting group.
 28. The process of claim 27, wherein the protecting group is an FMoc, CBz, or BOC protecting group.
 29. The process of any one of claims 26 to 28, wherein the protecting group is a BOC protecting group.
 30. A process for preparing a compound of formula V wherein PG is an amino protecting group, comprising reducing a compound of formula VI.


31. A process according to claim 30, in the presence of a reducing agent, in particular wherein the reducing agent is selected from the group consisting of borohydrides.
 32. A process for preparing a compound of formula VI comprising reacting a compound of formula VII with a compound of formula VII_(a) in the presence of base:

wherein PG is an amino protecting group.
 33. A process for preparing a compound of formula V, comprising: 1) reacting a compound of formula VII with a compound of formula VII_(a) to provide a compound of formula VI;

and 2) reducing a compound of formula VI with a reducing agent selected from the group consisting of borohydrides to provide a compound of formula V.


34. A process for the preparation of the compound of formula IV, comprising: 1) reacting a compound of formula VII with a compound of formula VII_(a) to provide a compound of formula VI;

2) reducing a compound of formula VI with a reducing agent selected from the group consisting of borohydrides to provide a compound of formula V;

and 3) deprotecting the azetidinyl ring of a compound of formula V to provide a compound of formula IV.


35. A process for the preparation of the compound of formula III, comprising: 1) reacting a compound of formula VII with a compound of formula VII_(a) to provide a compound of formula VI;

2) reducing a compound of formula VI with a reducing agent selected from the group consisting of borohydrides to provide a compound of formula V;

3) deprotecting the azetidinyl ring of a compound of formula V to provide a compound of formula IV;

and 4) reacting a compound of formula IV with a compound of formula IV_(a) to provide a compound of formula III.


36. A process for the preparation of the compound of formula II, comprising: 1) reacting a compound of formula VII with a compound of formula Vila to provide a compound of formula VI;

2) reducing a compound of formula VI with a reducing agent selected from the group consisting of borohydrides to provide a compound of formula V;

3) deprotecting the azetidinyl ring of a compound of formula V to provide a compound of formula IV;

4) reacting a compound of formula IV with a compound of formula IV_(a) to provide a compound of formula IIII;

and 5) hydrogenation of a compound of formula III to provide a compound of formula II.


37. A process for the preparation of the compound of formula I′, comprising: 1) reacting a compound of formula VII with a compound of formula VII_(a) to provide a compound of formula VI;

2) reducing a compound of formula VI with a reducing agent selected from the group consisting of borohydrides to provide a compound of formula V;

3) deprotecting the azetidinyl ring of a compound of formula V to provide a compound of formula IV;

4) reacting a compound of formula IV with a compound of formula IV_(a) to provide a compound of formula III;

5) hydrogenation of a compound of formula III to provide a compound of formula II;

and 6) reacting a compound of formula II with a compound of formula II_(a) to provide a compound of formula I′.


38. A process for the preparation of the compound of formula I′, comprising: a) hydrogenation of a compound of formula III to provide a compound of formula II;

and b) reacting a compound of formula II with a compound of formula II_(a) to provide a compound of formula I′.


39. A process for the preparation of the compound of formula I′, comprising: a) reacting a compound of formula IV with a compound of formula IV_(a) to provide a compound of formula III;

b) hydrogenation of a compound of formula III to provide a compound of formula II;

and c) reacting a compound of formula II with a compound of formula II_(a) to provide a compound of formula I′.


40. A process for the preparation of the compound of formula I′, comprising: a) deprotecting the azetidinyl ring of a compound of formula V to provide a compound of formula IV;

b) reacting a compound of formula IV with a compound of formula IV_(a) to provide a compound of formula III;

c) hydrogenation of a compound of formula III to provide a compound of formula II;

and d) reacting a compound of formula H with a compound of formula II_(a) to provide a compound of formula I′.


41. A process for the preparation of the compound of formula I′, comprising: a) reducing a compound of formula VI with a reducing agent selected from the group consisting of borohydrides to provide a compound of formula V;

b) deprotecting the azetidinyl ring of a compound of formula V to provide a compound of formula IV

c) reacting a compound of formula IV with a compound of formula IV_(a) to provide a compound of formula III;

d) hydrogenation of a compound of formula III to provide a compound of formula II;

and e) reacting a compound of formula II with a compound of formula II_(a) to provide a compound of formula I′.


42. A compound which is:

wherein PG is a protecting group;

wherein PG is an amino protecting group;

or


43. The compound of claim 42 which is a compound of formula V:

wherein PG is an amino protecting group.
 44. The compound of claim 37 which is a compound of formula VI:

wherein PG is an amino protecting group.
 45. The compounds of claim 43 or 44, wherein the amino protecting group is BOC.
 46. A compound of formula IV.


47. A compound of formula III.


48. A compound of formula II. 